The natural lens of the eye is contained within a capsular bag (in the present text, the terms “lens capsule”, “capsule”, “capsular bag” and “capsular sac” are used interchangeably), which is the basement membrane of lens epithelial cells held behind the iris and in front of the vitreous by the suspensory ligament called the zonules, and enveloping the natural lens. Capsular opacification (CO) is an opacification of the eye, which opacification is located on the inner surface of the capsular bag. It can be located posteriorly (posterior CO, PCO) and/or anteriorly (anterior CO, ACO). Capsular opacification can be caused by deposition or in-growth of cells, cell derivatives and/or fibers into the area that is transversed by the visual axis, and may also be caused by extra-cellular matrix that is produced by lens epithelial cells (in the following often referred to as LEC or LECs). The result is an occlusion of the optical axis of the eye and a concomitant clouding of vision. The cell deposits on the capsule (or on an implant that has replaced the lens) thus originate from the proliferation and migration of residual lens epithelial cells on the interior surface of the capsular bag, and from the production of extra-cellular matrix by these cells.
Capsular opacification often arises as a complication after surgical replacement of the natural lens of the eye with an implant. Such a replacement operation may be performed on patients suffering from cataracts, or in other circumstances. It is noted that lens removal with implantation replacement provides significant benefits to most cataract patients. Today, lens removal with implantation of artificial lenses is also increasingly carried out in non-cataractous eyes. An example is refractive lens exchange, which is often performed with the purpose of relieving presbyopia. Notwithstanding the usefulness of these operations, it is estimated that up to fifty percent of all patients who have had implants placed within the capsular bag will develop capsular opacification, also known as secondary cataract or after-cataract, within five years after surgery.
Extraction of the natural lens of the eye is among the most commonly performed operations in the world. In the following, a brief explanation of a common procedure will be given. In order to gain access to the natural lens, an incision is made in either the clear cornea, at the limbus, or in the sclera of the eye, whereby it becomes possible to introduce surgical instruments into the anterior segments of the eye. In the case of lens removal, an opening is made in the lens capsule, currently mainly using a capsulorhexis technique, in which a portion of the anterior membrane of the capsular bag is torn out to allow insertion of surgical instruments into the capsular bag for the purpose of extraction of the natural lens. The natural lens may be removed through application of any of a number of known techniques, including what is known as phacoemulsification. Phacoemulsification is a method that involves application of ultra-sonic energy, or other forms of energy, to the natural lens with the purpose of breaking said lens into fragments. The fragments may then be aspirated from the capsular bag. The capsular bag remains substantially intact throughout this process of lens removal, with the exception of the portion removed to prepare access for the surgical instruments used in the extraction of the natural lens. After the removal of the natural lens (aphakia), an artificial intraocular lens (IOL) implant may be implanted within the capsular bag in order to mimic the transparency and the refractive function of a natural lens. Alternatively, a lens material is injected to fill the capsular bag and to create an artificial lens in situ. In addition, such lenses (AOL, accommodative intraocular lenses) may have the ability to restore the accommodative function of the natural lens, after the onset of presbyopia (loss of ability to accommodate).
Ophthalmic surgeons, aware of the problems associated with residual lens epithelial cells, typically take considerable care in trying to remove as many of the LECs as possible, prior to implantation of an artificial lens (IOL or AOL). However, despite these efforts, a significant number of LECs are usually left on the interior surface of the capsular bag, since the cells are difficult to see and often difficult to reach and virtually impossible to completely remove.
The most common treatment for post-operative PCO is the use of laser energy, which is applied to the posterior membrane of the capsular bag for the purpose of creating an opening in the posterior capsule (this is known as Nd-YAG capsulotomy). However, the laser energy applied to the posterior membrane of the capsular bag is ordinarily directed through the implant, and might damage the optic of said implant. Accordingly, it is preferred to prevent the occurrence of CO rather than treating CO at a later date through the application of laser energy. This is especially desirable when the implant is accommodating in response to ciliary muscle contraction, in which case a laser capsulotomy may compromise the accommodative ability of the lens.
Various procedures for the prevention of CO have been suggested in recent years. Many such procedures have included the introduction of chemicals into the capsular bag in order to destroy residual lens epithelial cells. However, few, if any, of these procedures have proven to be particularly successful in the prevention of CO, due to the fact that it is extremely difficult to destroy residual LECs without simultaneously destroying other cells within the eye, e g there exists a number of chemical agents that could kill the lens epithelial cells, however, said agents may also adversely affect other cells with in the eye, in particular corneal endothelial cells. Thus, selective destruction of residual LECs by exploitation of the cells' increased proliferative activity has been the primary approach for the prevention of CO.
Antimetabolites, such as 5-fluorouracil (5-FU) and daunomycin, have been injected into the capsular bags of eyes in attempts to prevent CO. However, for antimetabolite therapy to be effective, the agents must be present when the residual lens epithelial cell proliferation resumes at an indeterminate time following surgery. Sustained drug delivery systems have also been investigated as means for preventing CO. However, the effective time frame within when to apply these agents may likewise be difficult to determine. Thus, timing is difficult in the prevention of CO since it, as mentioned above, is believed to result primarily from the propagation of residual lens epithelial cells of the germinal layer and it is difficult to accurately predict when said cells might start to proliferate and migrate across the capsular bag into the optical zone.
Patent application WO 02/15828 (Bausch and Lomb) discloses methods for removing epithelial cells by injecting a composition comprising an agent after the natural lens has been removed from the capsular bag. The disadvantage with this technique is that the capsular bag is empty, i e the whole capsular bag is thus filled with the composition. Thus, much agent is needed, and in case of leakage there is a great risk that many cells outside the capsular bag, in particular corneal endothelial cells, may be damaged. Furthermore, the agent is not concentrated to the region of the inner wall of the capsular bag where the CO can be expected to be most severe. Another disadvantage is that the reaction time is limited to the length of time that the attending surgeon is able to wait until proceeding with the surgery, e g by implanting a lens or injecting a lens-forming composition. Conventionally, this will not be more than just a few minutes. Most of the toxic substances known need more than a few minutes to have, at least, some effect on the lens epithelial cells. Many of them need much more time.
Other workers have taken a slightly different approach to solving the problem of CO. Thus, U.S. Pat. No. 6,186,148 deals with the use of a substance affecting focal contacts mediating contacts between cells, and describes injection of said substance into the lens capsule prior to removal of the natural lens. U.S. Pat. No. 4,909,784 discloses a similar technique, wherein a cell-killing substance is injected between the capsule and the natural lens. This injection also takes place before lens removal. In these circumstances, when cells are treated prior to lens removal, there is only a limited time available for the agent to perform its activity, since in general surgery must be finished quite promptly, as described above. Also, in these circumstances, it is not possible to direct the agent exclusively to those cells that will be left in the capsule after lens removal. In contrast, the agent is unnecessarily also applied to cells that are subsequently removed physically upon removal of the lens.
Thus, there exists a need for a relatively simple, reliable and effective method of preventing capsular opacification in patients implanted with artificial lenses following lens extraction.